A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma (COMBI-i)

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To evaluate the safety and efficacy of the combination of an anti-PD-1 antibody (Spartalizumab (PDR001)), a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in unresectable or metastatic BRAF V600 mutant melanoma

Part 1: Safety run-in Up to 18 evaluable patients with previously untreated unresectable or metastatic BRAF V600 mutated melanoma will be enrolled and treated at different dose levels to determine the recommended Phase 3 regimen of PDR001 in combination with dabrafenib and trametinib.

Part 2: Biomarker cohort Approximately 20 patients with previously unresectable or metastatic BRAF V600 mutated melanoma will be enrolled to describe changes in the immune microenvironment and biomarker modulations

Part 3: Randomized double blind Approximately 500 patients with previously untreated unresectable and metastatic BRAF V600 mutated melanoma will be enrolled to compare the anti-tumor activity of PDR001 in combination with dabrafenib and trametinib versus placebo plus dabrafenib and trametinib.

Biological: Spartalizumab (PDR001)

Spartalizumab (PDR001) will be supplied in vial in liquid or lyophilized pharmaceutical form. Spartalizumab (PDR001) will be administered via intravenous infusion over 30 minutes (up to 2 hours) once every 4 or 8 weeks.

Drug: Dabrafenib

Dabrafenib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Dabrafenib will be administered orally twice daily (150 mg BID) for Days 1-28 of a 28-day cycle.

Other Name: Tafinlar®

Drug: Trametinib

Trametinib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Trametinib will be administered orally once daily (2 mg QD) for Days 1-28 of a 28-day cycle.

Other Name: Mekinist®

Placebo Comparator: Placebo comparator arm

Matching placebo in combination with dabrafenib and trametinib

Other: Placebo

Placebo will be a Dextrose 5% in water (D5W) infusion supplied by the site.

Other Name: Placebo control

Drug: Dabrafenib

Dabrafenib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Dabrafenib will be administered orally twice daily (150 mg BID) for Days 1-28 of a 28-day cycle.

Other Name: Tafinlar®

Drug: Trametinib

Trametinib will be provided by the sponsor to the investigative site or supplied locally as commercially available. Trametinib will be administered orally once daily (2 mg QD) for Days 1-28 of a 28-day cycle.

Changes in PD-L1 levels and CD8+ cells upon treatment with Spartalizumab (PDR001) in combination with dabrafenib and trametinib

Randomized (Part 3): Progression-Free Survival (PFS), investigator assessed by RECIST 1.1 [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]

Progression-free survival is defined as the time from the date of first dose to the date of the first documented radiological progression using RECIST 1.1 response criteria

Secondary Outcome Measures :

Overall survival [ Time Frame: Up to death due to any cause (5 years) ]

Overall survival is defined as the time from date of randomization to date of death due to any cause

Overall response rate [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]

ORR is defined as the proportion of subjects with confirmed best overall response of complete response (CR) or partial response (PR), as per investigator's assessment by RECIST 1.1

Duration of response [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]

Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death, according to RECIST 1.1 criteria

Disease control rate [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]

Disease control rate is defined as the proportion of patients with CR or PR or subjects with SD lasting for a duration of at least 24 weeks as per local review according to RECIST 1.1 criteria

Global health status/quality of life score of the EORTC QLQ-C30 [ Time Frame: Up to 60 days post progression (5 years) ]

Patient's health-related quality of life

Global health status/quality of life score of the FACT-M subscale [ Time Frame: Up to 60 days post progression (5 years) ]

Patient's health-related quality of life

Global health status/quality of life score of the EQ-5D-5L [ Time Frame: Up to 60 days post progression (5 years) ]

Patient's health-related quality of life

Time to 10 point definitive deterioration in overall quality of life score from EORTC QLQ-C30 [ Time Frame: Up to 60 days post progression (5 years) ]

Patient's health-related quality of life

PFS by PD-L1 expression [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]

PFS analysis will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression.

Additionally PD-L1 subgroups will also be assessed using defined by a PD-L1 expression level cut-off of 10%, where a positive status is defined as having ≥ 10% expression and a negative status is defined as having < 10% expression.

OS by PD-L1 expression [ Time Frame: Up to disease progression or death due to any cause, whichever occurs first (5 years) ]

OS analysis will be performed by PD-L1 subgroup (positive, negative) where a positive status is defined as having ≥ 1% expression and a negative status is defined as having < 1% expression.

Additionally PD-L1 subgroups will also be assessed using defined by a PD-L1 expression level cut-off of 10%, where a positive status is defined as having ≥ 10% expression and a negative status is defined as having < 10% expression.

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